2-formyl androstanes and process therefor



Elite States PatentOfitice 3,577,434 Patented Feb. 12, 1953 3,077,484 2-FORMYL ANDRQSTANES AND PROQESS TEERBFOR Aihcrt Bowers, .iohn Edwards, and James C. on, all of Mexico tCity, Mexico, assignors, by mesue assignments, to Syntax Corporation, a corporation of Panama No Brewing. Filed Aug. '3, 1961, her. No. 128,971 Claims priority, application Mexico Apr. 12, 1961 23 Claims. (Cl. 260-39714) The present invention relates to certain new cyclopentanophenanthrene derivatives and to a method for-the preparation thereof. v

More particularly, our invention relates to the novel 2-formyl derivatives of androstan-l'iB-ol, which may further possess a lower 17e-alky1,alkenyloralkynylgroup; it also comprises the-preparation of the 'esters of such compounds and of the corresponding 19'-nor'derivatives.

These novel compounds are powerful anabolic agents having a favorable anabolic-androgenic ratio; they help to increase the protein metabolism and the deposition of calcium on the bone tissue; they further exhibit anti-estrogenic activity, lower the cholesterol level in the blood and inhibit the secretion of gonadotrophins by the pituitary gland.

The 17a-alkenyl and 17 u-alkyny-l compounds further posses progestational activity.

T he novel compounds of the present invention are represented by the following formula:

in the above formula R represents hydrogen or methyl, R represents hydrogen or an acyl group derived from a carboxylic acid of 1 to 12 carbon atoms; R represents hydrogen or a lower alkyl, alkenyl or alkynyl group such as methyl, ethyl, propyl, vinyl, ethynyl or propynyl. The

wavy line at (3-2 indicates the or B configuration for the tate, phenoxyacetate, cyclopentylpropionate and fl-chloropropionate.

V The novel compounds object of our invention are obtained by oxidation of the 2a and ZB-hydroxymethylandrostanes and l9-nor-androstanes, or by hydrogenation of the 2-formyl-A -androstenes and 19-nor-androstenes.

In our copending patent application Serial No. 128,972,

'filed on August 3, 1961, there is described the preparation of 2a and 2,8-hydroXymethyl-androstanes and their 17a-allryl, alkenyl and alkynyl substituted derivatives, as

well as the corresponding l9-nor derivatives.

In our copending patent application Serial No. 128,974, filed on August 3, 1961, there is described the preparation of Z-forrnyl-fi-androstenes starting from Z-alkoxymethylene derivatives of dihydroallotestosterone and 19-nordihydroallotestosterone, as well as from their l7a-alkyl,

alkenyl and alkynyl substituted derivatives, which upon reduction with a double metal hydride produce the corresponding Z-hydioxy compounds; the latter, upon acid treatment give rise to the formation of the 2-formyl-A androstenes and l9-nor-androstenes.

'alkenyl'and alkynyl substituted derivatives, are obtained by oxidation of an ester of 20a or 2,8-hydroxymethy1- androstan-17fi-ol or of their 19-n0r derivatives, with chromic acid in pyridine, at low temperature, preferably between 0' and 5 C., and for a period of time between 6 and 10 hours. By oxidation of 20: and Zfi-hydroxymethyl-l7ct-alkyl, alkenyl or alkynl androstan-17fi-ol, of the corresponding 19-nor compoundsor of an ester of the same, there are obtained the 20; and ZB-fcrmyl derivatives of 17a-alkyl, l7a-alkenyl and 17a-alknyl andros'tan-17/3-ol, the corresponding 19-nor derivatives and the esters of-the same.

Where the starting compound contains an ester group, this could be saponified by well known methods. The 17B-hydroxy-2e and 2,8-formyl-androstanes may be esterified with anhydrides or chlorides of acidsof 1 to 12 carbon atoms, in pyridine solution for the C-17ot unsubstituted compounds, or in benzene solution and in the presence of p-toluenesulfonic acid for the 17u-alkyl, alkenyl and alkynyl substituted derivatives.

'The Zuand ZB-formyl derivatives of androstan-17f3-ol and of 17ot alkyl-audrostan--01, as well as of the corresponding 19-nor compounds may also be obtained through the method illustrated by the following series of reactions:

and R represents hydrogen or a lower alkyl group.

By catalytic hydrogenation of 2-formyl-A -androsten- 17,8-01, 2-forrnyl-19-nor-A -androsten-17,8-01or one of their 17a-alkyl substituted derivatives (1), until the absorption of 1 molar equivalent of hydrogen, there are obtained the ZB-formyl-androstanes as well as the corresponding l9-nor-compounds (11). This hydrogenation is carried out in the presence of a palladium catalyst, such as 5% palladium on charcoal, 10% palladium on barium sulfate, 10% palladium on calcium carbonate, etc.

Suitable solvents for this reaction are ethyl acetate, ethanol, methanol, tetrahydrofuran and dioxane.

By alkaline treatment of the above compounds, using for example a dilute solution of sodium methoxide in methanol, 0.5% ethanolic potassium hydroxide, potassium t-butoxide in t-butanol, etc., there are obtained the 2a-forrnyl compounds (III). Thus, for example, by hydrogenation of 2-forrnyl-A -androsten-175-01 in ethyl acetate solution and in the presence of 5% palladium on charcoal, there is obtained Zfi-formyl-androstan-l718-01, which is converted into the 2ot-isomerby treatment with sodium methoxide.

2a formyl androstan 17,9 01 and 2c: formyl- 1.9-nor-androstan-l7p-ol may also be obtained by reducing a 2-lower alkoxymethylene-dihydroallotestosterone, preferably 2-methoxymethylene-dihydroaliotestosterone, (IV) and its 19-nor derivative with lithium aluminum hydride, thus giving 2-methoxymethylene-androstan-l7fl-ol and 2 methoxymethylene l9 nor androstan 17;? 01 (V). By hydrolysis of these compounds with perchloric acid in ether for a prolonged period of time, preferably for 16 to 24 hours, there are obtained Za-furmyl-androstan 17/8 01 and 20a formyl l9 nor androstan- 1718-01 (VI). The method described above is represented by the following series of reactions:

on on H, 12 i 0on3 R The following examples serve to illustrate but are not intended to limit the scope of the invention:

Example I A solution of 2 g. of 2tt-hydroxymethyll7a-methylandrostan 47 6-01 in 20 cc. of pyridine was treated with 1 g. of chromic acid in 10 cc. of pyridine and the mixture was kept at 0 C. for 10 hours, then diluted with ethyl acetate and filtered through celite; the filtrate was washed with hydrochloric acid solution, with sodium carbonate solution and with water to neutral, dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. Crystallization of the residue from acetone-ether yielded 2ot-formyl-17a-methyl-androstan-175- 01.

A mixture of 1 g. of 2a-formyl-17u-methyl-androstan- 17B-ol, 25 cc. of benzene, 2 cc. of acetic anhydride and 500 mg. of p-toluenesulfonic acid was kept at room temperature for 48 hours and then diluted with water; the benzene layer was separated, successively washed with 5% sodium carbonate solution and Water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was dissolved in 50 cc. of 0.5% methanolic potassium hydroxide solution, kept for 1 hour at room temperature, treated with water and extracted with ethyl acetate; the extract was washed to neutral, dried and evaporated to dryness under vacuum. By chromatography of the residue followed by crystallization of the solid fractions from acetone-ether there was obtained the acetate of 2a-formyl-17a-methy1-androstan- 1713-01.

Example II By following the method of oxidation described in the preceding example, 20: and ZB-hydroxymethyl-17e-ethynyl-19-nor-androstan-175-01 were respectively converted into Zwformyl-17a-ethynyl19-nor-androstan-l7fl-ol and 2 3-forn1yl-l7oc-ethynyl-l9-nor-androstan-l7B-ol.

Example HI By following the method of oxidation described in Example I, the hydroxymethyl compounds mentioned below in column I were converted into the corresponding 2- formyl derivatives (column I1).

2,9-formy1-17a-methyl-19-n0randrostan-l 75-01.

acetate of 25 formyl 17amethyl-androstan-UB-ol.

17-acetate of 2B-hydroxymethyl-l7a-methyl-androstan-17B- androstan-l'i'fl- Example IV A solution of 2.5 g. of Z-formyl-M-androsten-l7fl-ol in 50 cc. of ethyl acetate was hydrogenated at room temperature and atmospheric pressure in the presence of 500 mg. of 5% palladium on charcoal catalyst which had been previously reduced. After the uptake of 1 molar equivalent of hydrogen the catalyst was removed by filtration through celite and the filtrate was evaporated to dryness. Crystallization of the residue from methylene chloride-hexane afforded 2fi-formyl-androstan-17/3-01.

A mixture of 1 g. of the above compound, 5 cc. of pyridine and 2 cc. of benzoyl chloride was allowed to react overnight at room temperature, poured into water and the precipitate formed was collected, thus giving the benzoate of 2B-formyl-androstan-17fl-ol.

Example V A mixture of 1 g. of 2,8-formyl-androstan-17 8-01 and 25 cc. of a 0.5% solution of sodium methoxide was kept for 5 hours at room temperature and then poured into water. The precipitate formed was collected by filtration and crystallized from methylene chloride-hexane, thus furnishing Za-fOrmyI-androstan-l7fi-ol.

A mixture of 500 mg. of the above compound, 2 cc. of pyridine and 1 cc. of acetic anhydride was heated on the steam bath for 1 hour and poured into water; the precipitate formed was collected, thus giving the acetate of ZOt-fOImYl-EIIIdIOStHII-I7fi-Ol.

By the same method, but using caproic anhydride and undecenoic anhydride as esterifying agents there were obtained the caproate and the undecenoate of 2a-formylandrostan-17fi-ol.

Example Vl By following the method of hydrogenation described in Example IV, 2 g. of 2-formyl-17a-methyl-19-nor-A androsten-17B-ol was converted into 2fi-formyl-l7amethyl-19-nor-androstan-175-01, identical with the one obtained in Example 111.

Example VII A solution of 1 g. of 2-formyl-17a-ethyl-A -androsten- 175-01 in 25 cc. of tetrahydrofuran was hydrogenated in the presence of mg. of 10% palladium on barium sulfate, until the uptake of one molar equivalent of hydrogen. The catalyst was removed by filtration through celite and the filtrate was evaporated to dryness. By crystallization from acetone-hexane there was obtained 2fl-formyl-l7a-ethyl-androstan-l73-01.

300 mg. of the above compound was treated with sodium rnethoxide in methanol, in accordance with the method described in Example V, thus giving Za-formyll7a-ethyl-androstan-l75-01.

amuse Example VIII There was repeated the preceding Example, but using as starting compound 2-formyl-l9-nor-A -androsten-l7fi- 01, thus obtaining Z/B-formyl-19-nor-androstan-17B-ol and 2a-forrnyl-l9-nor-androstan-l7B-ol. Esterification of the latter compound with propionic anhydride in pyridine produced the propionate of Za-formyl-19-nor-androstanl7;8-ol.

Example IX A solution of 2 g. of 2-methoxymethylene-androstanl7fi-ol-3-one (obtained by esteri-fication of Z-hydroxymethylene-dihydroallotestosterone with diazomethane) in 50 cc. of tetrahydrofuran was cautiously added to 1 g. of lithium aluminum hydride in 100 cc. of anhydrous ether and the resulting mixture was refluxed for 16 hours. The mixture was cooled, the excess of anhydride was destroyed by the addition of methanol and after acidifying with dilute hydrochloric acid the organic layer was separated, Washed to neutral, dried over anhydrous sodium sulfate and evaporated to dryness. By crystallization of the residue from acetone-hexane there Was obtained 2-methoxymethylene-androstan-175-01.

To a solution of 500 mg. of the above compound in 50 cc. of ether was added 5 drops of 70% perchloric acid and the mixture was kept overnight at room temperature, then washed with water to neutral, dried over anhydrous sodium sulfate and evaporated until the product crystallized. There was thus obtained Za-formylandrostan-17B-ol, identical with the compound obtained in Example V.

In the same manner 2-methoxymethylene-19-nor-dihydroallotestosterone was converted into 2a-formyl-l9- nor-androstan-17e-o1, identical with that obtained in Example VIII. Esterification with undecenoic anhydride in pyridine afforded the undecenoate of 2a-formyl-19- nor-androstan-l7fi-ol.

Example X A solution of 2 g. of the propionate of 2fi-propionoxymethyl-17a-propargyl-androstan-17,8-01, obtained as described in our patent application Serial No. 128,972, filed on August 3, 1961, in 100 cc. of methanol was treated with 10 cc. of a 2% solution of potassium h droxide in methanol and the mixture was kept at 0 C. for 2 hours, then neutralized with acetic acid and concentrated to a small volume under vacuum. Water was added until complete precipitation of the product which was collected and crystallized from acetone-ether, thus giving the 17-pr0pionate of 2/3-hydroxymethyl-17a-propa1'gylandrostan-17fi-ol.

The above compound was oxidized with chromic acid in pyridine, in accordance with the method described in Example I, to produce the propionate of 2f3-formyl-17apropargyl-androstan-17,8-01.

We claim:

1. A compound of the following formula:

Cli

wherein R is selected from the group consisting of hydrogen and methyl; R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; and R is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl and lower alkynyl comprising oxidizing with chromic acid a compound of the following formula:

wherein R, R and R have the same meaning defined above at a low temperature.

21. A process for preparing a compound selected from the group consisting of Zfl-formyl-androstan--01, 2,8- forrnyl-l9-nor-androstan-17 8-01, 2,8 formyl l7u-lower alkyl-androstan-Ufi-ol and 2e-formyl-l7oc-lower alkyl-19- nor-androstan-Ufi-ol comprising hydrogenating the corresponding 2-formyl-A -androsten-175-01 compound in the presence of a. palladium catalyst until one molar equivalent of hydrogen is absorbed.

22. A process for preparing a compound selected from the group consisting of 2a-formyl-androstan-l'Ifi-ol, 2a- -formyl-l9-nor-androstan-l7 8-01, Za-fOrniyl 17cc lower alkyl-androstan-Ufi-ol and 2a-formyl-17e-lower alkyd-19- nor-androstan-Ufl-ol comprising reacting the corresponding 2 3-formyl derivative with an alkali metal lower alkoxide.

23. A process for preparing a 2a-formyl-androstan-l7eol derivative comprising reducing a 2-lower alkoxymethylenedihydroallotestosterone with lithium aluminum hydride and hydrolyzing the thus formed 2-lower alkoxymethylene-androstan-175-01 with acid for a prolonged period of time.

References Cited in the file of this patent UNITED STATES PATENTS 2,883,401 Babccck et a1. Apr. 21, 1959 

1. A COMPOUND OF THE FOLLOWING FORMULA: 